Acoustic Cluster Therapy Platform Boosts Tumor Shrinkage in Metastatic CRC

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Acoustic Cluster Therapy (ACT), a proprietary ultrasound-mediated drug delivery platform developed by EXACT Therapeutics, had a favorable safety profile and demonstrated enhanced local antitumor activity in patients with liver metastases from colorectal cancer (CRC), according to final data from the phase 1 ACTIVATE trial (NCT04021277).1

The final results affirm previously reported positive outcomes from ACTIVATE and indicate the added efficacy of ACT when combined with chemotherapy compared with chemotherapy alone. In patients who responded to chemotherapy, ACT-treated tumors experienced significantly greater tumor shrinkage than control tumors in the same patients (–29% vs –7%; P < .05).

In addition to confirming ACT’s clinical potential, the final analysis showed evidence of a dose-response relationship. Patients treated with 40 µl/kg of PS101, the ACT microbubble formulation, demonstrated significantly greater tumor shrinkage than those who received the formulation at 20 µl/kg. Among patients with chemotherapy-responsive control lesions, 3 of 4 individuals in the 40 µl/kg cohort experienced tumor shrinkage exceeding 30% in diameter. Overall, tumor shrinkage was observed in 6 of 9 patients who received ACT in combination with chemotherapy.

“I am excited about the data from the ACTIVATE trial, which yet again underscore the attractive therapeutic proposition from our proprietary ACT technology,” Per Walday, chief executive officer of EXACT Therapeutics, explained in a news release. “The strength of the response to treatment, the safety profile, and its non-invasive nature points to a unique and highly differentiated therapeutic regimen. We continue our efforts to bring ACT to [patients with] cancer as fast as possible. Building on the momentum of the ACTIVATE study, we are excited to be approaching the first patient dosing in our Phase 2 ENACT trial [NCT06850623] in locally advanced pancreatic cancer.”

ACTIVATE Trial Design and ACT Background

Treatment with ACT involves the intravenous administration of PS101, followed by targeted ultrasound insonation over the tissue of interest. PS101 is composed of microclusters consisting of perfluorobutane microbubbles and perfluoromethylcyclopentane microdroplets. Upon high-frequency ultrasound exposure, these microclusters coalesce into larger ACT bubbles that transiently lodge within the capillaries of the target area. Subsequent low-frequency insonation induces oscillation of the lodged bubbles, thereby enhancing the local delivery of concurrently administered chemotherapy to the targeted tissue.

ACTIVATE was a first-in-human, multicenter, open-label, single-arm trial that evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of ACT in combination with standard chemotherapy regimens—FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil, and irinotecan)—in patients with liver metastases from CRC.

Eligible patients were required to have histologically confirmed CRC with liver-dominant metastatic disease and be considered difficult to treat. Patients were enrolled across clinical sites in the United Kingdom and received systemic chemotherapy with either FOLFOX or FOLFIRI in conjunction with ACT.

A distinguishing feature of the ACTIVATE study design was its within-patient control model. Each patient had both ACT-treated lesions (insonation plus chemotherapy) and control lesions (chemotherapy alone without insonation), allowing for a direct intra-patient comparison of radiographic response. Tumor response assessments were performed at week 8 and evaluated via blinded independent central review in accordance with predefined imaging criteria.

A total of 11 patients were enrolled, of whom 9 were evaluable for efficacy. Patients received either 20 µl/kg or 40 µl/kg of PS101 to explore dose-response relationships. This approach enabled the assessment of localized treatment effects and minimized variability between individual patients.

The primary end points of the trial were the incidence of treatment-related adverse effects and dose-limiting toxicities.2 Secondary end points included preliminary antitumor activity at week 8, as well as best overall response.

Safety Overview

PS101 was found to be safe and well tolerated when administered in combination with chemotherapy in the ACTIVATE trial.1 No new safety signals were observed, and the overall safety profile was consistent with expectations based on the individual components of the regimen.

According to the news release, investigators have announced plans to present the full dataset from the ACTIVATE trial in a forthcoming scientific publication and at an upcoming medical conference.

“Today’s update marks the successful completion of the ACTIVATE trial. The results give us great confidence in the treatment potential of the ACT technology for patients with solid tumours," Amir Snapir, chief medical officer of EXACT Therapeutics, added in the news release.

References

1. EXACT Therapeutics announces positive final results in phase 1 ACTIVATE trial in liver metastases from colorectal cancer. News Release. EXACT Therapeutics. May 20, 2025. Accessed May 20, 2025. https://exact-tx.com/news-page/exact-therapeutics-announces-positive-final-results-in-phase-1-activate-trial-in-liver-metastases-from-colorectal-cancer
2. PS101-mediated ACT with chemotherapy in liver metastases from cancer of gastrointestinal origin (ACT). ClinicalTrials.gov. Updated October 10, 2024. Accessed May 20, 2025. https://clinicaltrials.gov/study/NCT04021277